Ewachiw, T. E. | Search bioRxiv

bioRxiv2026

TDP-43 Sustains Satellite Cells to Maintain and Regenerate Skeletal Muscle

Skeletal muscle satellite cells, residing between the myofiber plasma membrane and the surrounding basement membrane, maintain and repair skeletal muscle throughout life. Typically quiescent, satellite cells can transition into a reversible alert state (GAlert) that primes them for rapid activation to maintain or repair muscle. From GAlert, SCs can either re-enter quiescence or commit to the cell cycle, expand, and differentiate to fuse with existing regenerating myofibers. Exit from quiescence requires extensive post-transcriptional remodeling, including changes in RNA processing and RNA-binding protein activity. We show that TDP-43, an RNA binding protein, is essential for SC maintenance and muscle repair. Conditional deletion of TDP-43 in SCs caused a consistent and progressive loss of GAlert SCs even in uninjured muscle, leading to depletion of the SC pool. TDP-43 haploinsufficiency was sufficient to impair SC maintenance, indicating that both alleles are required. Integrative analysis suggests that TDP-43 supports expression of stress response-associated transcripts during the quiescent-to-GAlert transition, and that failure to mount this response contributes to SC apoptosis. Thus, we identified TDP-43 as a critical regulator of satellite cell survival as satellite cells activate and establish a TDP-43 requirement for maintaining and repairing skeletal muscle.

cell biology↗

bioRxiv2024

SREBP-dependent regulation of lipid homeostasis is required for progression and growth of pancreatic ductal adenocarcinoma

Metabolic reprogramming is a necessary component of oncogenesis and cancer progression that solid tumors undergo when their growth outstrips local nutrient supply. The supply of lipids such as cholesterol and fatty acids is required for continued tumor cell proliferation, and oncogenic mutations stimulate de novo lipogenesis to support tumor growth. Sterol regulatory element-binding protein (SREBP) transcription factors control cellular lipid homeostasis by activating genes required for lipid synthesis and uptake. SREBPs have been implicated in the progression of multiple cancers, including brain, breast, colon, liver, and prostate. However, the role the SREBP pathway and its central regulator SREBP cleavage activating protein (SCAP) in pancreatic ductal adenocarcinoma (PDAC) has not been studied in detail. Here, we demonstrated that pancreas-specific knockout of Scap has no effect on mouse pancreas development or function, allowing for examination of the role for Scap in the murine KPC model of PDAC. Notably, heterozygous loss of Scap prolonged survival in KPC mice, and homozygous loss of Scap impaired PDAC tumor progression. Using subcutaneous and orthotopic xenograft models, we showed that SCAP is required for human PDAC tumor growth. Mechanistically, chemical or genetic inhibition of the SREBP pathway prevented PDAC cell growth under low serum conditions due to a lack of lipid supply. Highlighting the clinical importance of this pathway, the SREBP pathway is broadly required for cancer cell growth, SREBP target genes are upregulated in human PDAC tumors, and increased expression of SREBP targets genes is associated with poor survival in PDAC patients. Collectively, these results demonstrate that SCAP and the SREBP pathway activity are essential for PDAC cell and tumor growth in vitro and in vivo, identifying SCAP as a potential therapeutic target for PDAC. SIGNIFICANCEOur findings demonstrate that SREBP pathway activation is a critical part of the metabolic reprogramming that occurs in PDAC development and progression. Therefore, targeting the SREBP pathway has significant therapeutic potential.

cancer biology↗